In the past purification and isolation of the compound of formulae I and II were achieved via a combination of several operations: extractions using solvents such as dichloromethane to remove residual organic solvents, chromatography using hydrophobic resins, nanofiltration for concentration of the process stream followed by crystallization of the pure drug. Several of these operations require high capital expenditure. In addition, the time-cycle of such a process is relatively long compromising the quality of the carbapenem product.
The object of the present invention is to teach a much simplified isolation protocol of the compound of formulae I and II via extractions with an alcohol with or without containing an appropriate ion-pairing reagent which concomitantly concentrates the carbapenem compounds followed by a direct crystallization of the product. The present invention is a more practical, efficient, safer and cost effective process because it eliminates the time consuming (and capital intensive) column purification and nanofiltration steps which can compromise the quality of the carbapenem compound due to degradation.
These and other objects will be apparent from the teachings contained herein.
A process for the direct crystallization of a compound of the formula I: 
or a pharmaceutically acceptable salt thereof, is disclosed, wherein R1 and R2 represent H, C1-10 alkyl, aryl or heteroaryl, or substituted C1-10 alkyl, aryl or heteroaryl and X+ represents a charge balancing group, comprising
extracting a solution containing a crude compound of formula I or Ia: 
or a pharmaceutically acceptable salt thereof, wherein each X+ is a charge balancing group, and R1 and R2 are as described above with a C4-10 alcohol, collecting and crystallizing the resulting aqueous phase to produce a crystalline compound of formula I.
Carbapenems can be prepared by coupling the, appropriate sidechain to a protected enolphosphate (3). In this reaction a base and solvent are used. The resulting crude product can then be deprotected to give the desired carbapenem in its crude form. In order to isolate this product in pure form via crystallization sideproducts and solvents need to be removed and the concentration of the product increased. In the past this has been typically achieved via a combination of extraction, column chromatography and nanofiltration.
It has now been discovered that the column chromatography and nanofiltration operations can be eliminated when the extraction is carried out with an appropriate alcohol. A preferred extraction is carried out with the appropriate alcohol in the presence of an ion-pairing reagent. The process described herein allows a direct crystallization of carbapenem compounds after this type of extraction. The process eliminates the column purification step and replaces the nanofiltration step for concentration of the carbapenem compound in preparation for the crystallization step.
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term xe2x80x9calkylxe2x80x9d refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight or branched, and when of sufficient size, e.g., C3115 may be cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl.
Alkyl also includes an alkyl group substituted with a cycloalkyl group, such as cyclopropylmethyl.
Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following: 
wherein: xxe2x80x2 and yxe2x80x2=from 0-10; and w and z=from 0-9.
The alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
Heteroalkyl means an alkyl group containing from 2-15 carbon atoms and being interrupted by from 1-4 heteroatoms selected from O, S and N.
The term xe2x80x9calkenylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
The term xe2x80x9calkynylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like. Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted as defined below. Preferred substituted aryls include phenyl and naphthyl substituted with one to three groups, such as selected from halo, alkyl and trifluoromethyl.
The term xe2x80x9cheteroarylxe2x80x9d refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms. The heteroaryl group is optionally substituted with up to three groups.
Heteroaryl includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine. Examples of partially aromatic groups are tetrahydroimidazo[4,5-c]pyridine, phthalidyl and saccharinyl, as defined below.
Substituted alkyl, aryl and heteroaryl, and the substituted portions of aralkyl, aralkoxy, heteroaralkyl, heteroaralkoxy and like groups are substituted with from 1-3 groups selected from the group consisting of: halo, hydroxy, cyano, acyl, acylamino, aralkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, alkyl, alkoxy, aryl, aryloxy, aralkoxy, amino, alkylamino, dialkylamino, carboxy and sulfonylamino.
The terms xe2x80x9cheterocycloalkylxe2x80x9d and xe2x80x9cheterocyclylxe2x80x9d refer to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S(O)y or N, and in which up to three additional carbon atoms may be replaced by said heteroatoms. When three heteroatoms are present in the heterocycle, they are not all linked together.
Examples of heterocyclyls are piperidinyl, morpholinyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolinyl, piperazinyl, pyrolidin-2-one, piperidin-2-one and the like.
Acyl as used herein refers to xe2x80x94C(O)C1-6 alkyl and xe2x80x94C(O)-aryl.
Acylamino refers to the group xe2x80x94NHC(O)C1-6 alkyl and xe2x80x94NHC(O)aryl.
Aralkoxy refers to the group xe2x80x94OC1-6 alkylaryl.
Alkaryl refers to C1-6 alkyl-aryl-.
Alkylsulfonyl refers to the group xe2x80x94SO2C1-6 alkyl.
Alkylsulfonylamino refers to the group xe2x80x94NHSO2C1-6alkyl.
Arylsulfonylamino refers to the group xe2x80x94NHSO2aryl.
Alkylaminocarbonyl refers to the group xe2x80x94C(O)NHC1-6 alkyl.
Aryloxy refers to the group xe2x80x94O-aryl.
Sulfonylamino refers to the group xe2x80x94NHSO3H.
Halo means Cl, F, Br and I selected on an independent basis.
Carbapenem I and II can be obtained as shown below in Flow Sheets A-1 and A-2 
Flow sheet A-2 below provides a preferred process as it relates to 1xcex2-methyl carbapenems. 
Compounds 3, 4 and 4xe2x80x2 can be obtained in accordance with techniques such as those disclosed in U.S. Pat. No. 5,034,384, granted on Jul. 23, 1991; U.S. Pat. No. 4,994,568 granted on Feb. 19, 1991; U.S. Pat. No. 4,269,772 granted on May 26, 1981; U.S. Pat. No. 4,350,631 granted on Sep. 21, 1982; U.S. Pat. No. 4,383,946 granted on May 17, 1983; U.S. Pat. No. 4,414,155 granted on Nov. 8, 1983; U.S. Serial No. 60/052032 (our case 19995PV), filed Jul. 9, 1997; Tet. Let. 21, 2783 (1980); J. Am. Chem. Soc. 108, 6161 (1980); J. Am. Chem. Soc. 108, 4675 (1986) and U.S. Pat. No. 5,478,820 granted on Dec. 26, 1995. The teachings of these references are incorporated herein by reference. Compounds of formula I and Ia and derivatives thereof and processes thereof are disclosed in U.S. Ser. No. 08/887,849 (our case 19735), filed Jul. 3, 1997 and U.S. Serial No. 60/049640 (our case 19760PV), filed Jun. 16, 1997.
The compounds of formula 5 or 5xe2x80x2 or salts thereof are produced by reacting the enol phosphate 3 and side chain precursor 4 or 4xe2x80x2 in the presence of a base. This reaction is typically conducted at reduced temperature, e.g., about xe2x88x9230xc2x0 C. to about xe2x88x9270xc2x0 C., preferably about xe2x88x9240xc2x0 C. to about xe2x88x9260xc2x0 C. Bases which are suitable for the above reaction include organic as well as inorganic bases. Preferred bases for use herein are secondary and tertiary amines as diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), guanidines such as 1,1,3,3-tetramethylguanidine (TMG), N,N,Nxe2x80x2,Nxe2x80x2Nxe2x80x3-tetraethylcyclohexylguanidine (TECHG), N,N,Nxe2x80x2,Nxe2x80x2-dicyclohexyldiethylguanidine (DCDEG) and amidines such as 1,8-diazabicyclo[4.3.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Most preferable bases are the guanidine bases and even more preferred is TMG.
The reaction can be conducted in an polar organic solvent, e.g., N-ethyl pyrrolidinone, N-methyl pyrrolidinone, N,N-dimethylformamide and the like. The preferred solvent is N-ethyl pyrrolidinone.
After coupling, the carbapenem is stabilized by combining the carbapenem with a carbon dioxide source. This provides a transient structure of formula 6 or 6xe2x80x2 where X+ represents a charge balancing counterion and P a protecting group. Examples of carbon dioxide sources include carbon dioxide gas, bicarbonates, such as sodium and potassium bicarbonate, and carbonates such as sodium and potassium carbonate. Stabilization can be conducted according to the teachings in U.S. Serial No. 60/049640 (our case 19760PV), filed Jun. 16, 1997, incorporated by reference herein.
Stabilization can be conducted under substantially neutral to slightly basic conditions, e.g., about pH 7.0 to about 8.5.
After stabilization, the carbapenem is subject to deprotection, thus removing the 3-carboxyl protecting group. The pyrrolidine nitrogen is maintained in the carbamate form during deprotection yielding Ia or IIa.
A preferred deprotection reaction is hydrogenolysis, which can be conducted using hydrogen gas or a compound which forms hydrogen.
Hydrogenolysis effectively removes the protecting group from the 3-carboxylate without substantially disrupting the xcex2-lactam ring or the stabilized carbamate form of the pyrrolidine amine.
Hydrogenolysis is typically conducted in the presence of a metal catalyst. The preferred reaction involves H2 gas with a palladium (Pd/C) catalyst. If necessary, base can be added. A preferred base is sodium hydroxide or sodium bicarbonate.
The stability of the pyrrolidine N-carbamate is pH dependent. The carbamate is readily converted to the unsubstituted pyrrolidine amine or ammonium salt under neutral to mildly acidic conditions. The extractions are preferably carried out under neutral or weakly basic conditions in order to maintain the stabilizing presence of the carbamate according to the teachings of WO 9745430. After the extractions are completed the pH is adjusted to produce I or II which are directly crystallized.
Carbon dioxide sources, as used herein, refer to carbon dioxide gas as well as compounds which produce carbon dioxide upon dissolution. Representative examples include carbonates and bicarbonates, such as sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. Preferably the carbonates and bicarbonates are used. Most preferably, the carbon dioxide source is sodium bicarbonate.
The carbon dioxide source can alternatively be included in the reaction medium prior to or during the deprotection reaction.
Other protecting groups which are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule, can be used. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with fluoride ion, treatment with a transition metal catalyst and a nucleophile, and catalytic hydrogenolysis.
Examples of suitable 3-carboxyl protecting groups are: benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl and t-butyl. A preferred carboxyl protecting group is p-nitrobenzyl.
Many other suitable protecting groups are known in the art. See, e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981 (Chapters 2 and 5).
Numerous salt-forming ions are recited in Berge, S. M., et al. J. Pharm. Sci. 66(1): 1-16 (1977), the teachings of which are incorporated herein by reference. The charge balancing group X, maintains overall charge neutrality. Preferably X represents a pharmaceutically acceptable salt forming cation.
Preferred salt-forming cations are selected from the group consisting of: sodium, potassium, calcium and magnesium.
More preferably the salt forming cation is a member selected from the group consisting of: Na+, Ca+2 and K+. 
The salt forming cations mentioned above provide electronic balance and overall charge neutrality. From zero to three positively charged counterions may be present, depending upon the number of charged moieties on the carbapenem. This is largely a function of pH, since at low pH, protonation of the negatively charged moieties may occur. Different counterions may also be included in the overall composition. Hence, for example, calcium and sodium could be included together in the pharmaceutical composition to provide overall charge neutrality. The counterions can thus be varied within wide limits. Generally the counterion or counterions are pharmaceutically acceptable cationic species.
The compounds formed in the present invention have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers. The processes of synthesizing all such isomers, including optical isomers, are included in the present invention.
In a preferred aspect of the invention a process for synthesizing a compound of the formula II 
or a pharmaceutically acceptable salt or ester thereof, is disclosed, wherein each X+ represents a charge balancing group, comprising extracting a solution containing a crude compound of formula II or IIa 
or a pharmaceutically acceptable salt thereof, wherein each X+ is a charge balancing group, with an alcohol, collecting and crystallizing the resultant aqueous phase to produce a crystalline compound of formula II. It is preferable that the extraction is conducted in the presence of an ion-pairing reagent and that pH of the aqueous phase is maintained between neutral and mildly basic pH. It is also preferable that the extraction is performed while II is stabilized in the form of IIa.
The alcohol useful for the present invention includes, but is not limited to, iso-amyl alcohol, tert-amyl alcohol, 1-butanol, 2-butanol, 1-octanol, 1-hexanol, 1-heptanol, cyclohexanol, 1-pentanol, cyclopentanol, 2-pentanol, 2-methyl-1-pentanol, 2-ethyl-1-butanol, 4-methyl-2-pentanol, 2,6-dimethyl-4-heptanol, 2-methylcyclohexanol, preferably 1-butanol or iso-amyl alcohol.
Preferred ion-pairing reagents for use in the present invention are lipophilic carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids and the like and their salts. Most preferred ion-pairing reagents are the sodium salts of diphenylphosphoric acid, stearic acid or dodecylbenzenesulfonic acid.
Using the process described herein the elimination of chromatographic and nanofiltration steps results in significant productivity gains reducing the overall time cycle and minimizing losses to degradation. In addition, high capital expenditures associated with chromatographic and nanofiltration steps are averted.